Chiral Ion-Pair Organocatalyst-Promoted Efficient Enantio-selective Reduction of α-Hydroxy Ketones

Article abstract of DOI:10.1002/adsc.201800053

The enantioselective reduction of α-hydroxy ketones with catecholborane has been developed employing 5 mol% of an 1,1′-bi-2-naphthol (BINOL)-derived ion-pair organocatalyst. This methodology provides a straightforward access to the corresponding aromatic 1,2-diols in high yields (up to 90%) with excellent enantioselectivities (up to 97%). Furthermore, the α-amino ketones also could be reduced with moderate ee values under mild reaction condition. (Figure presented.).

Full text of DOI:10.1002/adsc.201800053

Title: Chiral Ion-pair Organocatalyst Promoted Efficient Enantio-
selective Reduction of α-Hydroxy Ketones
Authors: Yiliang Zhang, Li He, and Lei Shi
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10.1002/adsc.201800053
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Chiral Ion-Pair Organocatalyst-Promoted Efficient Enantio-
selective Reduction of -Hydroxy Ketones
Yiliang Zhang,ab Li He,ab and Lei Shi*ab
a
Shenzhen Graduate School, Harbin Institute of Technology, Shenzhen 518055, China
MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemistry
b
and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, China. E-mail: lshi@hit.edu.cn, Web:
http://homepage.hit.edu.cn/pages/shilei
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
less investigated. So far, catecholborane has proved
Abstract. The enantioselective reduction of -hydroxy
ketones with catecholborane has been developed employing to be one of the most versatile and robust achiral
boron hydrides,[11] which also shows a significant
5 mol% of an 1,1’-bi-2-naphthol (BINOL)-derived ion-pair
organocatalyst.
This
methodology
provides
a
tolerance for many functional groups. There are only
a few examples of asymmetric organocatalysis
processes using catecholborane as reductant. In 1998,
Fujisawa[12] developed a method of the asymmetric
reduction of (trifluoroacetyl)biphenyl derivatives
using oxazaborolidine catalyst and catecholborane. In
2000, Umani-Ronchi[13] demonstrated the use of
Zn(OTf)2-bisoxazoline complexes for the catalytic
enantioselective reduction of -alkoxy ketones. A
few years ago, Falck and Antilla successfully utilized
catecholborane in the reduction of ketones employing
either thiourea catalysts or chiral phosphoric acids,
respectively.[14] Later on, Enders and co-workers
reported the use of catecholborane in the
organocatalytic asymmetric transfer hydrogenation of
a range of ketimines[15] and -ketone esters[16] with
good results via Brønsted acid catalysis. To the best
of our knowledge no asymmetric reduction of -
hydroxy ketones employing achiral borane hydrides
has been developed.
straightforward access to the corresponding aromatic 1,2-
diols in high yields (up to 90%) with excellent
enantioselectivities (up to 97%). Furthermore, the -amino
ketones also could be reduced with moderate ee values
under mild reaction condition.
Keywords: -hydroxy ketone; ion-pair; catecholborane;
organocatalysis; reduction
Catalytic asymmetric reduction of carbonyl
compounds is one of the most sophisticated methods
in organic synthesis.[1] Although Significant progress
has been made in the asymmetric transfer
hydrogenation
of
aromatic
ketones,[2]
the
development of a general and asymmetric catalytic
method applicable to the synthesis of optically active
1,2-diols still meets a great challenge. These
compounds are known as substructures of many
naturally occurring or pharmaceutical compounds
such as carisbamate,[3a] reboxetine,[3b] and many other
biologically active substances.[3c-d]
Over the last decade, along with the rapid
development of organocatalysis, chiral-ion pair have
emerged as
a
new and efficient type of
organocatalysts.[17] Inspired by previous work,[18] and
also in conjunction with our ongoing interest in the
asymmetric reduction,[19] we present herein a chiral
ion-pair organocatalyst-promoted enantioselective
hydroboration of -hydroxy ketones.
Chiral 1,2-diols have commonly been synthesized
by direct asymmetric dihydroxylation of alkenes,[4]
asymmetric hydrolysis of epoxides,[5] enzymatic
reactions,[6] and asymmetric hydrogenation of -
hydroxy ketones.[7-9] Among various synthetic
methods, the last one represents the most direct and
promising approaches for the generation of valuable
terminal, vicinal 1,2-diols. While many highly
enantioselective processes catalyzed by transition-
metal complexes based on Ir,[7] Rh,[8] and Ru[9] have
been reported, additional studies using organocatalyst
to achieve highly enantioselective hydrogenation of
-hydroxy ketones are still warranted.
We started our investigations with evaluation of
representative chiral phosphoric acids 4 and 5 for the
reduction of the commercially available 2-hydroxy-1-
phenylethan-1-one 1a at room temperature. Initial
tests with the SPINOL-derived phosphoric acids 4
were not very promising, the desired 1-phenylethane-
1,2-diol 6a was mostly obtained in moderate yields
and low enantioselectivities. We then examined
BINOL-derived phosphoric acids (5a, 5d, 5e etc.) in
this reaction, which unfortunately also gave diol 6a in
low enantioselectivities or even as racemic mixtures
(Table 1). Increasing the steric demand of the aryl
Although achiral boranes are already widely used
in the CBS-reduction,[10] the use of achiral boron
hydrides as reducing agents in organocatalysis is still
1
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10.1002/adsc.201800053
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction conditions.a)
Table 2. Optimization of the additive.a)
Entry
Additive (mol %)
Yield ee(
(%)b)
%)c)
1
2
3
-
85
87
89
88
90
78
62
75
54
66
83
95
90
57
Ca(OMe)2 (2.5)
Mg(t-Bu)2 (2.5)
DMAP (5.0)
DMAP (5.0)
4
5 d)
6 d)
7 d)
N,N-diethylpyridin-4-amine (5.0)
4-(pyridin-4-yl)morpholine (5.0)
N,N-diphenethylpyridin-4-mine
(5.0)
Entry catalyst
Solvent
T(°C)
Yield( ee(%)
8 d)
67
68
c)
%)b)
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
55
85
73
62
47
68
65
70
32
53
45
76
23
80
72
58
<5
0
75
55
0
5
-3
-12
-15
-10
-23
60
53
5
72
79
81
-
(R)-5a
(R)-5b
(R)-5c
(R)-5d
(R)-5e
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
(R)-5b
(R)-5b
(R)-5b
(R)-5b
(R)-5b
(R)-5b
(R)-5b
9
10
11
Phenylboronic Acid (5.0)
p-Tolylboronic Acid (5.0)
4-Chlorophenylboronic Acid (5.0)
63
56
54
81
70
65
a)
Reaction condition: 1a (0.1 mmol), catalyst (R)-5b (5
mol %), additive (x mol %), MgSO4(100 mg) and 1.6 e.q
catecholborane 3 in 1 mL toluene. Unless otherwise noted,
the reaction was carried out under nitrogen at r.t for 4 h.
Yield of isolated product after column chromatography.
b)
c)
d)
9
Determined by HPLC analysis. Reaction was run at -
78°C for 4h.
10
11
12
13
14
15
16
17
DCM
formations,[17, 20] an investigation on the influence of
different types of additives in the reaction was
commenced (Table 2). Firstly, phosphoric acid metal
salts of calcium and magnesium showed the results of
good yields with enantioselectivities decreased to
54%
enantioselectivity was obtained when combining
chiral phosphate acid with 4-
c-hexane
o-xylol
toluene
toluene
toluene
r.t
-20
-55
-78
a) Reaction condition: 1a (0.1 mmol), catalyst (5 mol %),
MgSO4 (100 mg) and 1.6 e.q catecholborane 3 in 1 mL
solvent. Unless otherwise noted, the reaction was carried
and
66%,
respectively.
Excellent
b)
out under nitrogen for 12 h. Yield of isolated product
after column chromatography.
analysis.
(dimethylamino)pyridine (DMAP) (Table 2, entry 4–
5), which has been proved to be an efficient
combination in previous work.[14b] However, other
potential candidates for cation moiety, such as N,N-
diethylpyridin-4-amine, 4-(pyridin-4-yl)morpholine
and N,N-diphenethylpyridin-4-mine, did not further
improve the ee value (Table 2, entries 6–8).
Furthermore, boronic acids were also evaluated as
additives,[21] which seem to have a negligible effect
on enantioselectivities (Table 2, entries 9–11).
With the optimal anionic and cationic moiety of
the catalyst identified, we further examined the
influence of the amount of catecholborane 3 in the
reaction (Table 3). Drawing on the experience of
other reduction protocols employing catecholborane
as the reducing agent,[13-16] we found the use of 1.8
equiv of hydride source provided the best result with
96% ee (Table 3, entry 4), while lowering the amount
of borane led to a significant decrease of yield and ee
value. Especially under low temperature, an extra
amount (more than 1.6 equiv) of catecholborane 3 is
very important to maintain the enantioselectivity in
this reaction.
c)
Determined by HPLC
substituents on the BINOL backbone using catalysts
5c caused the enantioselectivity to increase
dramatically to 55%. Finally, the best result was
obtained with BINOL-derived phosphoric acid 5b,
furnishing the product in 85% yield and 75% ee.
Screening polar or inert solvent like DCM or diethyl
ether revealed inferior enantioselectivities compared
to toluene (Table 1, entries 11–12). Whereas using c-
hexane as solvent only led to a low enantioselectivity
of 5% (Table 1, entries 13), conducting the reaction
in o-xylol furnished diol 6a with 72% ee. The best
result was obtained using toluene as solvent under the
same condition, instead, the selectivity clearly
increased to 75% ee and even more when the reaction
mixture was cooled to -20°C and -55°C (Table 1,
entries 15–16). But when the reaction temperature
reached -78°C, catalyst 5b show very low catalytic
activity due to low temperature. Later on, we found
out that when DMAP was added, the reaction
proceeded smoothly even at -78°C with good yields
and ee values (Table 2, entry 4).
With the optimized conditions in hand, the scope
of the reaction was studied. Various electron-rich as
well as electron-deficient aromatic -hydroxy
ketones 1 with different substitution patterns
furnished the resulting diols 6 with good yields and
enantioselectivities. The absolute configuration of the
Since phosphoric acid metal salts and phosphoric
acid derived ion-pair catalysts have already been
reported to be effective in numerous organic trans-
2
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10.1002/adsc.201800053
Advanced Synthesis & Catalysis
Table 3. Influence of the amount of catecholborane 3 on
Table 5. Substrate scope of -amino ketones. a)
reduction.a)
Entry
3 (equiv)
Yield
(%)b)
ee(%)c)
1
2
3
4
5
1.0
1.4
1.6
1.8
2.0
50
65
90
89
86
30
57
95
96
92
a) Reaction condition: 1a (0.1 mmol), catecholborane 3 (x
equiv), DMAP (5 mol %), catalyst (R)-5b (5 mol %),
MgSO4 (100 mg) in 1 mL toluene at -78°C for 4h. b) Yield
c)
a) Reaction condition: 2 (0.1 mmol), catecholborane 3 (1.8
equiv), DMAP (5 mol %), catalyst (S)-4e (5 mol %),
MgSO4 (100 mg) in 1 mL toluene. Unless otherwise noted,
the reaction was carried out under nitrogen in toluene at -
20 °C for 2 h, yields referred to isolated yields, ee values
were determined by HPLC.
of isolated product after column chromatography.
Determined by HPLC analysis.
aromatic 1,2-diols 6 has been determined to be (S) by
comparing the optical rotation values with those re-
ported in the literature.[4e, 9f] Interestingly, electron-
rich -hydroxy ketones (1d and 1e) gave inferior
enantioselectivties but still in good yields,
halogenated, substrates gave better results. Moreover,
ketones bearing halogen substituents in both 3 and 4-
position of the aromatic ring gave slightly higher
enantioselectivities than other substitution patterns
(Table 4, 6p–6r). With decreasing size the halogen
atom in the 4-position of the phenyl ring the
enantioselectivity increased from 60% for iodine (see
in SI) to 95% for chlorine substituted -hydroxy
ketone 1i. To our delight more sterically demanding
ketones (1l and 1m) were reduced in high yields with
very good selectivities (90% ee). Labile functional
groups, such as nitrile, trifluoromethyl, and trifluoro-
methoxy were well tolerated (Table 4, 6p–6r).
Heteroaromatic systems could be reduced smoothly
with good yields, albeit with only moderate
selectivities of 71% ee and 57% ee, respectively.
Furthermore, aromatic diol 6u bearing
a
substituent in the 2-position were isolated in
moderate enantioselectivity. We suspected that the
ortho substituents might interfere with the preferred
coordination of the carbonyl group to the boron cen-
Table 4. Substrate scope of -hydroxy ketones. a)
a) Reaction condition: 1 (0.1 mmol), catecholborane 3 (1.8 equiv), DMAP (5 mol %), catalyst (R)-5b (5 mol %), MgSO4
(100 mg) in 1 mL toluene. Unless otherwise noted, the reaction was carried out under nitrogen at -78 °C for 2 h, Yields
referred to isolated yields, ee values were determined by HPLC. b) Reaction was run at -20°C.
3
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10.1002/adsc.201800053
Advanced Synthesis & Catalysis
before the addition of dry toluene (1.0 mL). The mixture
was allowed to stir for 30 min before being cooled to -
ter and lead to low selectivity. When employing the
optimal conditions, moderate selectivity was obtained
for 3-hydroxy-1-phenylpropan-1-one 1v, but still in
good yield. Finally we use methylated ketone 1w
asubstrate, albeit with only moderate selectivity. The
OH group of the -hydroxy ketones might be
essential to control the enantioselectivity under the
existing conditions of this reaction.
78 °C. Catecholborane
3 (1.8 equiv) was added
subsequently. After stirring for 2 h at -78 °C, MeOH (0.5
mL) followed by 1N NaOH solution (1 mL) were added.
The mixture was allowed to warm to room temperature
gradually and stirred for another 1 h and then extracted
with EtOAc (10 mL ×3), dried over Na2SO4 and
concentrated in vacuo. The residue was purified by silica
gel column chromatography.
We next turned our attention to asymmetric
reduction of -amino ketones 2, and the results were
presented in Table 5. Unfortunately, the
corresponding products 7a-7d were obtained in
moderate enantioselectivities (Table 5).[22]
Acknowledgements
We sincerely thank the “Hundred Talents Program” of Harbin
Institute of Technology (HIT), the “Fundamental Research Funds
for the Central University” (HIT.BRETIV.201502), the NSFC
(21202027), the NCET (NCET-12-0145), and the “Technology
Foundation for Selected Overseas Chinese Scholar” of Ministry
of Human Resources and Social Security of China (MOHRSS) for
funding.
On the basis of aforementioned results and
previous reports,[13b, 14a] a possible mechanism for this
reaction is proposed (Scheme 1). On the basis of the
fact that the hydrogen evolution is observed after
mixing the chiral ion-pair catalyst with
catecholborane 3, therefore, a chiral phosphoryl
borate intermediate (TS) is thought to be formed.
While the boron of the intermediate can act as a
Lewis acid coordinating to the ketone, the P=O
moiety the catalyst coordinates to another
catecholborane molecule. The hydride of this
catecholborane can be added in a chiral environment
of the -hydroxy ketones, providing the (S)-
configured diols and regenerated the catalyst.
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Scheme 1. Proposed reaction mechanism.
In summary, we have found that chiral ion-pair
(comprised of chiral phosphoric acid and DMAP) can
act as an efficient organocatalyst for asymmetric
reduction of -hydroxy ketones. The scalable
protocol furnished the chiral diols in good yields and
excellent enantioselectivities. Further investigations
utilizing this catalytic system are ongoing in our lab.
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General procedure for asymmetric reduction ：
To a flame-dried test tube was added catalyst (2r,6s)-
2,6-di(anthracen-9-yl)-4-hydroxydinaphtho[1,3,2]dioxaph-
osphepine 4-oxide (R)-5b (3.5 mg, 0.005 mmol, 5 mol %),
4-(dimethylamino)-pyridine (DMAP, 1.2 mg, 0.005 mmol,
5 mol %) and 1.0 mL dry CH2Cl2, stirred for 1h and then
concentrated in vacuo to form the ion-pair catalyst. 2-
Hydroxy ketone 1 (0.10 mmol) and MgSO4 (100 mg) were
added in the tube. The vessel was placed under vacuum
and the atmosphere exchanged with nitrogen three times
4
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10.1002/adsc.201800053
Advanced Synthesis & Catalysis
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COMMUNICATION
Chiral Ion-Pair Organocatalyst-Promoted Efficient
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Yiliang Zhang,ab Li He,ab and Lei Shi*ab
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